Influence of Daytime LED Light Exposure on Circadian Regulatory Dynamics of Metabolism and Physiology in Mice.

Light is a potent biologic force that profoundly influences circadian, neuroendocrine, and neurobehavioral regulation in animals. Previously we examined the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit more light in the blue-appearing portion of the visible spectrum (465 to 485 nm) than do broad-spectrum cool white fluorescent (CWF) light, on the nighttime melatonin amplitude and circadian regulation of metabolism and physiology. In the current studies, we tested the hypothesis that exposure to blue-enriched LED light at day (bLAD), compared with CWF, promotes the circadian regulation of neuroendocrine, metabolic, and physiologic parameters that are associated with optimizing homeostatic regulation of health and wellbeing in 3 mouse strains commonly used in biomedical research (C3H [melatonin-producing], C57BL/6, and BALB/c [melatonin-non-producing]).

Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer.

Disruption of circadian time structure and suppression of circadian nocturnal melatonin (MLT) production by exposure to dim light at night (dLAN), as occurs with night shift work and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of breast cancer and resistance to tamoxifen and doxorubicin. Melatonin inhibition of human breast cancer chemoresistance involves mechanisms including suppression of tumor metabolism and inhibition of kinases and transcription factors which are often activated in drug-resistant breast cancer. Signal transducer and activator of transcription 3 (STAT3), frequently overexpressed and activated in paclitaxel (PTX)-resistant breast cancer, promotes the expression of DNA methyltransferase one (DNMT1) to epigenetically suppress the transcription of tumor suppressor Aplasia Ras homolog one (ARHI) which can sequester STAT3 in the cytoplasm to block PTX resistance.

Effects of Daytime Exposure to Light from Blue-Enriched Light-Emitting Diodes on the Nighttime Melatonin Amplitude and Circadian Regulation of Rodent Metabolism and Physiology.

Regular cycles of exposure to light and dark control pineal melatonin production and temporally coordinate circadian rhythms of metabolism and physiology in mammals. Previously we demonstrated that the peak circadian amplitude of nocturnal blood melatonin levels of rats were more than 6-fold higher after exposure to cool white fluorescent (CWF) light through blue-tinted (compared with clear) rodent cages. Here, we evaluated the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit light rich in the blue-appearing portion of the visible spectrum (465-485 nm), compared with standard broadspectrum CWF light, on melatonin levels during the subsequent dark phase and on plasma measures of metabolism and physiology.

Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth.

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts.

PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome.

Although PIWI-interacting RNAs (piRNAs) account for the largest class of the small non-coding RNA superfamily, virtually nothing is known of their function in human carcinogenesis. Once thought to be expressed solely in the germ line where they safeguard the genome against transposon-induced insertional mutations, piRNAs are now believed to play an active role in somatic gene regulation through sequence-specific histone modification and DNA methylation. In the current study, we investigate the role of piRNA-021285 (piR-021285) in the regulation of the breast cancer methylome.

The circadian gene CRY2 is associated with breast cancer aggressiveness possibly via epigenomic modifications.

Although the role of core circadian gene cryptochrome 2 (CRY2) in breast tumorigenesis has been demonstrated, the correlations of CRY2 with clinical parameters in breast cancer patients and its involvement in epigenetic processes such as DNA methylation remain relatively unexplored. In the current study, we first queried the Oncomine database and the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) database to identify associations between CRY2 expression levels and clinical parameters in breast cancer patients. We then silenced CRY2 in vitro and performed a genome-wide methylation array to determine the epigenetic impact of CRY2 silencing.

The influence of red light exposure at night on circadian metabolism and physiology in Sprague-Dawley rats.

Early studies on rodents showed that short-term exposure to high-intensity light (> 70 lx) above 600 nm (red-appearing) influences circadian neuroendocrine and metabolic physiology. Here we addressed the hypothesis that long-term, low-intensity red light exposure at night (rLEN) from a 'safelight' emitting no light below approximately 620 nm disrupts the nocturnal circadian melatonin signal as well as circadian rhythms in circulating metabolites, related regulatory hormones, and physi- ologic parameters. Male Sprague-Dawley rats (n = 12 per group) were maintained on control 12:12-h light:dark (300 lx; lights on, 0600) or experimental 12:12 rLEN (8.

Targetome profiling and functional genetics implicate miR-618 in lymphomagenesis.

Despite the voluminous body of observational evidence concerning the role of miRNAs in cancer, significant knowledge gaps remain concerning the molecular circumstances that underlie the miRNA-cancer connection. In this study, we employ a multidisciplinary approach to establish an association between miR-618 and non-Hodgkin lymphoma (NHL) in a human population and attempt to explicate this association at the molecular level. A high-throughput, transcriptome-wide RIP-Chip-based method was used to identify members of the miR-618 targetome, which were analyzed for functional relevance using a gene network-based approach.

Diabetes mellitus and colorectal cancer prognosis: a meta-analysis.

Background: Diabetes mellitus is associated with an increased incidence of colorectal cancer, but the impact of diabetes mellitus on colorectal cancer prognosis is not clear.

Objective: We conducted a meta-analysis of observational studies to examine the association between preexisting diabetes mellitus and colorectal cancer all-cause mortality, cancer-specific mortality, and recurrence.

Data Sources: Medline and Embase were searched through August 22, 2012.

Advanced sleep schedules affect circadian gene expression in young adults with delayed sleep schedules.

Background: Human circadian rhythms are regulated by the interplay between circadian genes and environmental stimuli. The influence of altered sleep-wake schedules or light on human circadian gene expression patterns is not well characterized.

Methods: Twenty-one young adults were asked to keep to their usual sleep schedules and two blood samples were drawn at the end of the first week from each subject based on estimated time of dim light melatonin onset (DLMO); the first sample was obtained one and a half hours before the estimated DLMO and the second three hours later, at one and a half hours after the estimated DLMO.

Association of AMP-activated protein kinase with risk and progression of non-Hodgkin lymphoma.

Background: Metabolic dysregulation has been identified as an "emerging hallmark" of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis.

Methods: We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non-Hodgkin lymphoma (NHL).

Targetome profiling, pathway analysis and genetic association study implicate miR-202 in lymphomagenesis.

Background: miRNAs have been implicated in numerous tumorigenic pathways, and previous studies have associated miR-202 dysregulation with various cancer types, including follicular lymphoma.

Methods: The miR-202 targetome was identified by ribonucleoprotein immunoprecipitation-microarray (RIP-Chip), and functional interactions among identified targets were investigated using the Ingenuity Pathway Analysis tool. We also conducted a population-based genetic association study of a polymorphism within the miR-202 stem-loop sequence and risk of non-Hodgkin lymphoma.

Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways.

Background: Melatonin, a hormone-like substance involved in the regulation of the circadian rhythm, has been demonstrated to protect cells against oxidative DNA damage and to inhibit tumorigenesis.

Results: In the current study, we investigated the effect of melatonin on DNA strand breaks using the alkaline DNA comet assay in breast cancer (MCF-7) and colon cancer (HCT-15) cell lines. Our results demonstrated that cells pretreated with melatonin had significantly shorter Olive tail moments compared to non-melatonin treated cells upon mutagen (methyl methanesulfonate, MMS) exposure, indicating an increased DNA repair capacity after melatonin treatment.

Epigenetic impact of long-term shiftwork: pilot evidence from circadian genes and whole-genome methylation analysis.

Epigenetic association studies have demonstrated differential promoter methylation in the core circadian genes in breast cancer cases relative to cancer-free controls. The current pilot study aims to investigate whether epigenetic changes affecting breast cancer risk could be caused by circadian disruption through exposure to light at night. Archived DNA samples extracted from whole blood of 117 female subjects from a prospective cohort conducted in Denmark were included in this study.

Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk.

Results from recent molecular epidemiologic studies suggest that the core circadian genes play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. In order to further evaluate this hypothesis, we conducted a genetic and epigenetic association study of the circadian regulator TIMELESS in breast carcinogenesis. We detected significant associations between two tagging SNPs (rs2291738 and rs7302060) in the TIMELESS gene and breast cancer among 441 breast cancer cases and 479 cancer-free controls, with apparent effect modification by ER/PR status.

Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis.

Given strong evidence implicating an important role of altered microRNA expression in cancer initiation and progression, the genes responsible for microRNA biogenesis may also play a role in tumorigenesis. Exportin-5 (XPO5) is responsible for exporting pre-miRNAs through the nuclear membrane to the cytoplasm, and is thus critical in miRNA biogenesis. In the current study, we performed both genetic and epigenetic association studies of XPO5 in a case control study of breast cancer.

Phenotypic effects of the circadian gene Cryptochrome 2 on cancer-related pathways.

Background: Circadian genes continue to gain attention as important transcriptional regulators with the potential to influence a variety of biological pathways, including many cancer-related processes. The core circadian gene cryptochrome 2 (CRY2) is essential for proper circadian timing, and is a key component of the negative arm of the circadian feedback loop. As such, aberrant expression of CRY2 may influence carcinogenic processes and thereby impact cancer susceptibility.

The core circadian gene Cryptochrome 2 influences breast cancer risk, possibly by mediating hormone signaling.

As transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer.

CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses.

The transcription factors responsible for maintaining circadian rhythm influence a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis.

Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study.

Circadian genes are responsible for maintaining the ancient adaptation of a 24-hour circadian rhythm and influence a variety of cancer-related biological pathways, including the regulation of sex hormone levels. However, few studies have been undertaken to investigate the role of circadian genes in the development of prostate cancer, the most common cancer type among men (excluding nonmelanoma skin cancer). The current genetic association study tested the circadian gene hypothesis in relation to prostate cancer by genotyping a total of 41 tagging and amino acid-altering single nucleotide polymorphisms (SNP) in 10 circadian-related genes in a population-based case-control study of Caucasian men (n = 1,308 cases and 1,266 controls).

The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression.

microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis.

Increasing evidence has suggested that microRNAs (miRNA) play an important role in tumorigenesis. As transcriptional regulators, altered miRNA expression may affect many cancer-related biological pathways, indicating that miRNAs can function as tumor suppressors and/or oncogenes. We first performed a genetic association analysis by screening genetic variants in 15 miRNA genes and detected that a common sequence variant in hsa-miR-196a-2 (rs11614913, C-->T) was significantly associated with decreased breast cancer risk (for homozygous variant: odds ratio, 0.

Clock-cancer connection in non-Hodgkin's lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome 2.

Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non-Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL.

The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response.

Apart from regulating sleep and wakefulness, the circadian system may play an important role in other biological processes, including pathways involved in tumorigenesis. Two genetic association studies recently conducted by our lab have shown that a missense mutation in neuronal PAS domain protein 2 (NPAS2), a core circadian gene and transcriptional regulator, is significantly associated with risk of breast cancer and non-Hodgkin's lymphoma. Our current functional analyses provide the first in vitro evidence further demonstrating that cells with RNA interference-mediated depletion of NPAS2 fail to exhibit the expected cell cycle delay in response to mutagen treatment.